A model was developed to interpret the binding of drugs and physiological substances to plasma proteins to determine how this binding effects the brain uptake of highly bound substances. The model was applied to bilirubin to assess kernicterus in infants. Melphalan, an anticancer alkylating agent, was measured in the blood and brain of rats and its pharmacokinetics determined. It enters the brain via an amino acid transport system at the blood- brain barrier; its entry is related to its plasma protein binding, which is concentration-dependent. The blood-brain barrier could be opened in rats and mice by intracarotid infusion of a hypertonic arabinose solution. The rate of reclosure was related to the size of the intravascular tracer, indicating that tight junctions between cerebrovascular endothelial cells were modified. Reversible osmotic barrier opening was used to deliver interferon to the brain of rats.